3,4-methylenedioxymethamphetamine (MDMA) is an important drug of abuse. Recent evidence indicates that MDMA can be neurotoxic to serotonergic (5-HT) systems in the brains of rats and nonhuman primates. However, it is unknown to what extent a functional impairment is associated with the neurochemical changes. Since the central nervous system is the predominant regulator of neuroendocrine function, with pituitary secretion of ACTH and prolactin being strongly influenced by 5-HT pathways in the brain, a potential functional measure of neurotoxicity would be to assess changes in the ACTH and prolactin response to 5-HT probes as well as to acute stress. Preliminary data in humans and animals indicate that exposure to MDMA does produce persistent neuroendocrine changes. The relationship between neurotoxicity, as assessed by neurochemical changes, and functional impairment, as measured by the neuroendocrine responses to 5-HT agonists and stress, will be determined over time in rats exposed to different dosages of MDMA. The threshold doses of MDMA necessary to produce functional alterations will be determined. The results of these studies will help to elucidate the pathophysiologic sequelae that can result from exposure to this drug of abuse, as well as guide future research studies of comparable nature in humans.